The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming

Abed Alfatah Mansour; Ohad Gafni; Leehee Weinberger; Asaf Zviran; Muneef Ayyash; Yoach Rais; Vladislav Krupalnik; Mirie Zerbib; Daniela Amann-Zalcenstein; Itay Maza; Shay Geula; Sergey Viukov; Liad Holtzman; Ariel Pribluda; Eli Canaani; Shirley Horn-Saban; Ido Amit; Noa Novershtern; Jacob H. Hanna

doi:10.1038/nature11272

The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming

Abed Alfatah Mansour, Ohad Gafni, Leehee Weinberger, Asaf Zviran, Muneef Ayyash, Yoach Rais, Vladislav Krupalnik, Mirie Zerbib, Daniela Amann-Zalcenstein, Itay Maza, Shay Geula, Sergey Viukov, Liad Holtzman, Ariel Pribluda, Eli Canaani, Shirley Horn-Saban, Ido Amit, Noa Novershtern, Jacob H. Hanna

Medicine - Cardiology Division

Research output: Contribution to journal › Review article › peer-review

298 Scopus citations

Abstract

Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by ectopic expression of different transcription factors, classically Oct4 (also known as Pou5f1), Sox2, Klf4 and Myc (abbreviated as OSKM). This process is accompanied by genome-wide epigenetic changes, but how these chromatin modifications are biochemically determined requires further investigation. Here we show in mice and humans that the histone H3 methylated Lys27 (H3K27) demethylase Utx (also known as Kdm6a) regulates the efficient induction, rather than maintenance, of pluripotency. Murine embryonic stem cells lacking Utx can execute lineage commitment and contribute to adult chimaeric animals; however, somatic cells lacking Utx fail to robustly reprogram back to the ground state of pluripotency. Utx directly partners with OSK reprogramming factors and uses its histone demethylase catalytic activity to facilitate iPSC formation. Genomic analysis indicates that Utx depletion results in aberrant dynamics of H3K27me3 repressive chromatin demethylation in somatic cells undergoing reprogramming. The latter directly hampers the derepression of potent pluripotency promoting gene modules (including Sall1, Sall4 and Utf1), which can cooperatively substitute for exogenous OSK supplementation in iPSC formation. Remarkably, Utx safeguards the timely execution of H3K27me3 demethylation observed in embryonic day 10.5g-11 primordial germ cells (PGCs), and Utx-deficient PGCs show cell-autonomous aberrant epigenetic reprogramming dynamics during their embryonic maturation in vivo. Subsequently, this disrupts PGC development by embryonic day 12.5, and leads to diminished germline transmission in mouse chimaeras generated from Utx-knockout pluripotent cells. Thus, we identify Utx as a novel mediator with distinct functions during the re-establishment of pluripotency and germ cell development. Furthermore, our findings highlight the principle that molecular regulators mediating loss of repressive chromatin during in vivo germ cell reprogramming can be co-opted during in vitro reprogramming towards ground state pluripotency.

Original language	English (US)
Pages (from-to)	409-413
Number of pages	5
Journal	Nature
Volume	488
Issue number	7411
DOIs	https://doi.org/10.1038/nature11272
State	Published - Aug 16 2012

Bibliographical note

Funding Information:
Acknowledgements J.H.H. is supported by a generous gift from Ilana and Pascal Mantoux, The Sir Charles Clore Research Prize, an ERC starting investigator grant (StG-2011-281906), the Israel Science Foundation Regular and Bikura research grants,theICRF Foundation, Fritz Thyssen Stiftung, the AlonFoundationscholar award, a grant from E. A. and R. Drake, and the Leona M. and Harry B. Helmsley Charitable Trust. N.N. and A.P. are supported by Weizmann Dean fellowship awards. We thank A. Smith, H. Niwa and M. Saitou for reagents. We thank the Weizmann Institute management for providing critical financial and infrastructural support.

Publisher link

10.1038/nature11272

Find It

Find It at U of M Libraries

Cite this

Mansour, A. A., Gafni, O., Weinberger, L., Zviran, A., Ayyash, M., Rais, Y., Krupalnik, V., Zerbib, M., Amann-Zalcenstein, D., Maza, I., Geula, S., Viukov, S., Holtzman, L., Pribluda, A., Canaani, E., Horn-Saban, S., Amit, I., Novershtern, N., & Hanna, J. H. (2012). The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature, 488(7411), 409-413. https://doi.org/10.1038/nature11272

Mansour, AA, Gafni, O, Weinberger, L, Zviran, A, Ayyash, M, Rais, Y, Krupalnik, V, Zerbib, M, Amann-Zalcenstein, D, Maza, I, Geula, S, Viukov, S, Holtzman, L, Pribluda, A, Canaani, E, Horn-Saban, S, Amit, I, Novershtern, N & Hanna, JH 2012, 'The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming', Nature, vol. 488, no. 7411, pp. 409-413. https://doi.org/10.1038/nature11272

@article{c2a7cdb397f74c4e8a340345f0429725,

title = "The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming",

abstract = "Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by ectopic expression of different transcription factors, classically Oct4 (also known as Pou5f1), Sox2, Klf4 and Myc (abbreviated as OSKM). This process is accompanied by genome-wide epigenetic changes, but how these chromatin modifications are biochemically determined requires further investigation. Here we show in mice and humans that the histone H3 methylated Lys27 (H3K27) demethylase Utx (also known as Kdm6a) regulates the efficient induction, rather than maintenance, of pluripotency. Murine embryonic stem cells lacking Utx can execute lineage commitment and contribute to adult chimaeric animals; however, somatic cells lacking Utx fail to robustly reprogram back to the ground state of pluripotency. Utx directly partners with OSK reprogramming factors and uses its histone demethylase catalytic activity to facilitate iPSC formation. Genomic analysis indicates that Utx depletion results in aberrant dynamics of H3K27me3 repressive chromatin demethylation in somatic cells undergoing reprogramming. The latter directly hampers the derepression of potent pluripotency promoting gene modules (including Sall1, Sall4 and Utf1), which can cooperatively substitute for exogenous OSK supplementation in iPSC formation. Remarkably, Utx safeguards the timely execution of H3K27me3 demethylation observed in embryonic day 10.5g-11 primordial germ cells (PGCs), and Utx-deficient PGCs show cell-autonomous aberrant epigenetic reprogramming dynamics during their embryonic maturation in vivo. Subsequently, this disrupts PGC development by embryonic day 12.5, and leads to diminished germline transmission in mouse chimaeras generated from Utx-knockout pluripotent cells. Thus, we identify Utx as a novel mediator with distinct functions during the re-establishment of pluripotency and germ cell development. Furthermore, our findings highlight the principle that molecular regulators mediating loss of repressive chromatin during in vivo germ cell reprogramming can be co-opted during in vitro reprogramming towards ground state pluripotency.",

author = "Mansour, {Abed Alfatah} and Ohad Gafni and Leehee Weinberger and Asaf Zviran and Muneef Ayyash and Yoach Rais and Vladislav Krupalnik and Mirie Zerbib and Daniela Amann-Zalcenstein and Itay Maza and Shay Geula and Sergey Viukov and Liad Holtzman and Ariel Pribluda and Eli Canaani and Shirley Horn-Saban and Ido Amit and Noa Novershtern and Hanna, {Jacob H.}",

note = "Funding Information: Acknowledgements J.H.H. is supported by a generous gift from Ilana and Pascal Mantoux, The Sir Charles Clore Research Prize, an ERC starting investigator grant (StG-2011-281906), the Israel Science Foundation Regular and Bikura research grants,theICRF Foundation, Fritz Thyssen Stiftung, the AlonFoundationscholar award, a grant from E. A. and R. Drake, and the Leona M. and Harry B. Helmsley Charitable Trust. N.N. and A.P. are supported by Weizmann Dean fellowship awards. We thank A. Smith, H. Niwa and M. Saitou for reagents. We thank the Weizmann Institute management for providing critical financial and infrastructural support.",

year = "2012",

month = aug,

day = "16",

doi = "10.1038/nature11272",

language = "English (US)",

volume = "488",

pages = "409--413",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7411",

}

TY - JOUR

T1 - The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming

AU - Mansour, Abed Alfatah

AU - Gafni, Ohad

AU - Weinberger, Leehee

AU - Zviran, Asaf

AU - Ayyash, Muneef

AU - Rais, Yoach

AU - Krupalnik, Vladislav

AU - Zerbib, Mirie

AU - Amann-Zalcenstein, Daniela

AU - Maza, Itay

AU - Geula, Shay

AU - Viukov, Sergey

AU - Holtzman, Liad

AU - Pribluda, Ariel

AU - Canaani, Eli

AU - Horn-Saban, Shirley

AU - Amit, Ido

AU - Novershtern, Noa

AU - Hanna, Jacob H.

N1 - Funding Information: Acknowledgements J.H.H. is supported by a generous gift from Ilana and Pascal Mantoux, The Sir Charles Clore Research Prize, an ERC starting investigator grant (StG-2011-281906), the Israel Science Foundation Regular and Bikura research grants,theICRF Foundation, Fritz Thyssen Stiftung, the AlonFoundationscholar award, a grant from E. A. and R. Drake, and the Leona M. and Harry B. Helmsley Charitable Trust. N.N. and A.P. are supported by Weizmann Dean fellowship awards. We thank A. Smith, H. Niwa and M. Saitou for reagents. We thank the Weizmann Institute management for providing critical financial and infrastructural support.

PY - 2012/8/16

Y1 - 2012/8/16

N2 - Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by ectopic expression of different transcription factors, classically Oct4 (also known as Pou5f1), Sox2, Klf4 and Myc (abbreviated as OSKM). This process is accompanied by genome-wide epigenetic changes, but how these chromatin modifications are biochemically determined requires further investigation. Here we show in mice and humans that the histone H3 methylated Lys27 (H3K27) demethylase Utx (also known as Kdm6a) regulates the efficient induction, rather than maintenance, of pluripotency. Murine embryonic stem cells lacking Utx can execute lineage commitment and contribute to adult chimaeric animals; however, somatic cells lacking Utx fail to robustly reprogram back to the ground state of pluripotency. Utx directly partners with OSK reprogramming factors and uses its histone demethylase catalytic activity to facilitate iPSC formation. Genomic analysis indicates that Utx depletion results in aberrant dynamics of H3K27me3 repressive chromatin demethylation in somatic cells undergoing reprogramming. The latter directly hampers the derepression of potent pluripotency promoting gene modules (including Sall1, Sall4 and Utf1), which can cooperatively substitute for exogenous OSK supplementation in iPSC formation. Remarkably, Utx safeguards the timely execution of H3K27me3 demethylation observed in embryonic day 10.5g-11 primordial germ cells (PGCs), and Utx-deficient PGCs show cell-autonomous aberrant epigenetic reprogramming dynamics during their embryonic maturation in vivo. Subsequently, this disrupts PGC development by embryonic day 12.5, and leads to diminished germline transmission in mouse chimaeras generated from Utx-knockout pluripotent cells. Thus, we identify Utx as a novel mediator with distinct functions during the re-establishment of pluripotency and germ cell development. Furthermore, our findings highlight the principle that molecular regulators mediating loss of repressive chromatin during in vivo germ cell reprogramming can be co-opted during in vitro reprogramming towards ground state pluripotency.

AB - Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by ectopic expression of different transcription factors, classically Oct4 (also known as Pou5f1), Sox2, Klf4 and Myc (abbreviated as OSKM). This process is accompanied by genome-wide epigenetic changes, but how these chromatin modifications are biochemically determined requires further investigation. Here we show in mice and humans that the histone H3 methylated Lys27 (H3K27) demethylase Utx (also known as Kdm6a) regulates the efficient induction, rather than maintenance, of pluripotency. Murine embryonic stem cells lacking Utx can execute lineage commitment and contribute to adult chimaeric animals; however, somatic cells lacking Utx fail to robustly reprogram back to the ground state of pluripotency. Utx directly partners with OSK reprogramming factors and uses its histone demethylase catalytic activity to facilitate iPSC formation. Genomic analysis indicates that Utx depletion results in aberrant dynamics of H3K27me3 repressive chromatin demethylation in somatic cells undergoing reprogramming. The latter directly hampers the derepression of potent pluripotency promoting gene modules (including Sall1, Sall4 and Utf1), which can cooperatively substitute for exogenous OSK supplementation in iPSC formation. Remarkably, Utx safeguards the timely execution of H3K27me3 demethylation observed in embryonic day 10.5g-11 primordial germ cells (PGCs), and Utx-deficient PGCs show cell-autonomous aberrant epigenetic reprogramming dynamics during their embryonic maturation in vivo. Subsequently, this disrupts PGC development by embryonic day 12.5, and leads to diminished germline transmission in mouse chimaeras generated from Utx-knockout pluripotent cells. Thus, we identify Utx as a novel mediator with distinct functions during the re-establishment of pluripotency and germ cell development. Furthermore, our findings highlight the principle that molecular regulators mediating loss of repressive chromatin during in vivo germ cell reprogramming can be co-opted during in vitro reprogramming towards ground state pluripotency.

UR - http://www.scopus.com/inward/record.url?scp=84865112255&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865112255&partnerID=8YFLogxK

U2 - 10.1038/nature11272

DO - 10.1038/nature11272

M3 - Review article

C2 - 22801502

AN - SCOPUS:84865112255

SN - 0028-0836

VL - 488

SP - 409

EP - 413

JO - Nature

JF - Nature

IS - 7411

ER -

The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming

Abstract

Bibliographical note

Publisher link

Find It

Other files and links

Fingerprint

Cite this